Acetyl coenzyme-A carboxylases (ACC) catalyze the rate limiting reaction in fatty acid biosynthesis in plants and animals. ACC is a biotin containing enzyme which catalyzes the carboxylation of acetyl CoA to form malonyl CoA in a two-step reaction. Beaty and Lane, J. Biol. Chem. 1982, 257:924 929. The first step is the ATP-dependent carboxylation of biotin covalently linked to the enzyme. In the second step, a carboxyltransferase step, the carboxyl group is transferred to the substrate, acetyl CoA, to form malonyl CoA.
Malonyl-CoA is an intermediate substrate that plays an important role in the overall fatty acid metabolism: malonyl-CoA is utilized (as C2 donor) by fatty acid synthase for de novo synthesis of long chain fatty acids, and also acts as a potent allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1), a mitochondrial membrane protein that shuttles long chain fatty acyl CoAs into the mitochondria where they are oxidized. Ruderman N. and Prentki M, Nat Rev Drug Discov. 2004; 3:340-51. An inhibitor of ACC would thus limit de novo lipid synthesis, de-inhibit CPT1 and subsequently increase fat oxidation.
In mammals, there are two known isoforms of acetyl CoA carboxylase (ACC) that are encoded by distinct genes and share approximately 70% amino acids identity. ACC1(ACCα), a 265 KD protein, is highly expressed in the cytosol of lipogenic tissues such as liver and adipose tissue, where fatty acids are synthesized. ACC2 (ACCβ), a 280 KD protein, is expressed mainly in oxidative, non-lipogenic, tissues, such as skeletal muscle and heart muscle, although some is also found in liver. Mao J. et al., Proc Natl Acad Sci USA, 2003, 100:7515-20; Abu-Elheiga L. et al., J Biol Chem 1997; 272:10669-77. Malonyl CoA produced by ACC1 is preferentially converted into fatty acids by fatty acid synthase. Abu-Elheiga L. et al., Proc Natl Acad Sci USA 2000; 97:1444-9.
The malonyl CoA postulated to be formed by ACC2 locally on the mitochondrial surface regulates the palmitoyl CoA shuttle system. Abu-Elheiga L. et al., Proc Natl Acad Sci USA 2000; 97:1444-9. Malonyl CoA is a potent inhibitor of carnitine palmitoyl transferase 1 (CPT-1), and as a consequence, it decreases the fatty acid flux into the mitochondria. Thus, reduction of ACC2 activity would reduce local malonyl CoA levels and increase fatty acid β-oxidation concomitantly reducing triacylglycerol (TAG) synthesis. Munday, Biochem Soc Trans. 2001 30:1059-64; Yamauchi T. et al. Nat Med 2001; 7:941-6.
ACC is a potential target in metabolic diseases, such as metabolic syndrome, obesity, insulin resistance, dyslipidemia, diabetes, atherosclerosis, and cardiovascular diseases, which are mediated by abnormal fatty acid metabolism. An inhibitor of ACC would potentially limit de novo lipid synthesis, de-inhibit CPT1 and subsequently increase fat oxidation. Increased rates of muscle fatty acid oxidation, a reduced fat content and a reduction in total body fat were observed in ACC-2 knock-out mice (Abu-Elheiga et al., Science 2001, 291:2613 2616; Abu-Elheiga et al., Proc. Natl. Acad. Sci. USA, 2003 100:10207 10212). Harwood et al. reported that ACC inhibitors caused reduction in fatty acid synthesis, increase in fatty acid oxidation, and reduction of respiratory quotient in rats. Harwood et al., J. Biol. Chem. 2003, 278:37099 37111. Chronic dosing of these compounds resulted in the reduction of whole body fat mass and improvement of insulin sensitivity. Harwood et al., J. Biol. Chem. 2003, 278:37099 37111. These observations further validated the enzyme as a drug target.
Several non-natural product small molecule have been identified which target ACC for the prophylaxis or treatment of metabolic syndrome, atherosclerosis, diabetes, and obesity, see, U.S. Pat. No. 6,979,741, US Applications No. 2007/0219258, No. 2007/0219251, and No. 2003/0187254. There is a continuing need and a continuing search in this field of art for more potent therapeutic agents.